Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:30]=[CH:31][CH:32]=2)O1>>[CH3:18][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([N:33]5[CH2:34][CH2:35][O:36][CH2:37][CH2:38]5)[CH:28]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCC1
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCOCC5)c4)nc23)CCCC1

Procedure:
(1-Methyl-cyclopentyl)-[2-(3-morpholin-4-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclopentyl)-methanone and 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine following general procedures as described in these Examples. M+H=391.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][CH2:21][NH:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)[N:14]=[CH:13]2)=[O:9])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.CS(C)=O.[C:39]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52](ON1C(=O)CCC1=O)=[O:53])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>CN(C)C=O>[C:42]([O:41][C:39]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52]([NH:1][CH:2]([CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][CH2:21][NH:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)[N:14]=[CH:13]2)=[O:9])[C:3]([OH:5])=[O:4])=[O:53])=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: NC(CNC(=O)c1ccc2c(cnn2CCCNc2ncc[nH]2)c1)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)NC(CNC(=O)c1ccc2c(cnn2CCCNc2ncc[nH]2)c1)C(=O)O
Reaction time: 0.08 h
Yield: 66.3 %

Procedure:
2-Amino-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid (0.050 g, 0.103 mmol) was dissolved in N,N-dimethylformamide (2 mL). Triethylamine (43.1 μL, 0.309 mmol) was added and the reaction was stirred for 5 minutes. A precipitate formed so methyl sulfoxide (1 mL) was added. Succinimidyl N-boc-6-aminohexanoate (0.0406 g, 0.124 mmol) was added and the reaction was stirred under N2 for 18 h. The reaction was then concentrated to an oil under high vacuum. The oil was purified by the following method (Preparative HPLC Method A) to give 39.9 mgs (66%) of product. ESMS: Calcd. for C28H40N8O6, 584.31. Found, 585.2 [M+H]+1. Analytical HPLC, Method B, Rt=18.72 min, Purity=98% Preparative HPLC Method A:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCc1ccc(Cl)cc1
Product: O=[N+]([O-])c1cnc2ccccc2c1NCc1ccc(Cl)cc1

Procedure:
Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 4-chlorobenzylamine to provide yellow solid 4-(4-chlorobenzylamino)-3-nitroquinoline, melting point of crude product 168°-173° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][N:4]=1.Br[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([CH:45]([CH3:47])[CH3:46])=[C:41]([CH3:48])[CH:40]=2)=[O:37])[CH:31]=1.C([O-])([O-])=O.[K+].[K+]>CCO.C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:45]([C:42]1[CH:43]=[CH:44][C:39]([NH:38][C:36]([C:32]2[CH:31]=[C:30]([C:6]3[CH:5]=[N:4][C:3]([O:2][CH3:1])=[C:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:7]=3)[CH:35]=[CH:34][N:33]=2)=[O:37])=[CH:40][C:41]=1[CH3:48])([CH3:47])[CH3:46]
Reactant: Cc1cc(NC(=O)c2cc(Br)ccn2)ccc1C(C)C
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NC(=O)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ncc(-c2ccnc(C(=O)Nc3ccc(C(C)C)c(C)c3)c2)cc1NC(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of benzyl (2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)carbamate (180 mg, 0.47 mmol) in EtOH (4 mL) and toluene (16 mL) was added 4-bromo-N-(4-isopropyl-3-methylphenyl)picolinamide (0.23 g, 0.70 mmol), Pd(PPh3)4 (5.4 mg, 0.046 mmol), and 2M K2CO3 in water (0.46 mL). The mixture was stirred at 100° C. overnight under nitrogen. After cooling to room temperature and evaporation of the solvent, the residue was purified by combi-flash (ISCO, 40 g silica, UV254, 3:1 pet ether/ethyl acetate) to afford benzyl (2′-((4-isopropyl-3-methylphenyl)carbamoyl)-6-methoxy-[3,4′-bipyridin]-5-yl)carbamate (216 mg, 90% yield) as a yellow solid: MS (ES) m/z 511 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1.[C:32]([O:35][CH2:36][CH2:37]Br)(=[O:34])[CH3:33].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:32]([O:35][CH2:36][CH2:37][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=2)[N:23]=[C:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:34])[CH3:33]
Reactant: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2Cc2ccccc2O)c1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2Cc2ccccc2OCCOC(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution consisting of 2-[[2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridin-1-yl]methyl]phenol (Compound of Example 157) (41 mg), bromoethyl acetate (18 mg), N,N-dimethyl formamide (1 ml) was added potassium carbonate (19 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain [2-[[2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridin-1-yl]methyl]phenoxy]ethyl acetate (37 mg, 74%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([S:12]([NH2:15])(=[O:14])=[O:13])[CH3:11])([O-:3])=[O:2].C(N=[C:21]=[O:22])CCC.N12CCN(CC1)CC2.C(Cl)(Cl)=O>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([S:12]([N:15]=[C:21]=[O:22])(=[O:13])=[O:14])[CH3:11])([O-:3])=[O:2]
Reactant: CC(c1ccccc1[N+](=O)[O-])S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: CC(c1ccccc1[N+](=O)[O-])S(=O)(=O)N=C=O

Procedure:
A mixture of 16 g of the product from Example 14, 8.0 ml of n-butyl isocyanate, and 0.2 g of 1,4-diazabicyclo[2.2.2]octane (DABCO) in 125 ml dry xylenes was heated to 130°-135° C. for 11/2 hours. To this solution was added 6 ml of phosgene at a rate which maintained the temperature above 130° C. After completion of the addition (ca. one hour), the solution was cooled and filtered under nitrogen. The filtrate was concentrated in vacuo to give the crude 1-(2-nitrophenyl)ethanesulfonyl isocyanate as a viscous orange oil. The IR spectrum of this compound displayed a characteristic isocyanate absorption at 2240 cm-1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH3:9][C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1>CCO>[CH3:9][C@H:10]1[NH:11][CH2:12][CH2:13][N:14]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH2:15]1
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1ccc(Cl)nc1
Solvent: CCO
Product: Cc1ccc(N2CCN[C@H](C)C2)nc1

Procedure:
A solution of 2-chloro-5-methyl-pyridine (127 mg, 1 mmoles), (2R)-2-methyl-piperazine (200 mg, 2 mmoles) in EtOH (3 mL) was heated in microwave to 180° C. for 5 minutes. The mixture was cooled, concentrated under reduced pressure and partitioned with DCM and the saturated aqueous sodium bicarbonate layer. The aqueous solution was extracted three times with additional DCM. The combined organic extracts were washed twice with water, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide the crude title compound.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:9](=O)[CH:10]=[C:11]([CH3:16])[C:12](=[O:15])[C:13]=1[CH3:14].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[N:18]=[C:9]1[CH:10]=[C:11]([CH3:16])[C:12]([OH:15])=[C:13]([CH3:14])[CH:8]1[CH3:7]
Reactant: CC1=CC(=O)C(C)=C(C)C1=O
Reactant: Nc1nccs1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CC1=CC(=Nc2nccs2)C(C)C(C)=C1O
Temperature: 25 °C
Yield: 15 %

Procedure:
Pyridine (3.24 ml) was dissolved in 120 ml of dichloroethane, followed by addition of 1.10 ml of titanium tetrachloride. The mixture was heated under reflux for 15 minutes. Then, 3.00 g of 2,3,5-trimethyl-1,4-benzoquinone and 2.00 g of 2-aminothiazole were added, and the resultant mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and filtered through a Celite pad, and the insoluble matter was washed with chloroform. The filtrate was concentrated, and the crude product obtained was purified by silica gel column chromatography (diethyl ether-hexane =1:19 1:4) to give 0.70 g of 4-(2-thiazolylimino)-2,3,6-trimethylphenol as a pale red solid melting at 95°-96° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[C:19]1([CH2:29][C:30](O)=[O:31])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:30](=[O:31])[CH2:29][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cccc2ccccc12
Product: O=C(Cc1cccc2ccccc12)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(naphthalen-1-yl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.18 (d, J=8.2 Hz, 1H), 7.87-8.04 (m, 5H), 7.49-7.62 (m, 4H), 4.15 (s, 2H), 3.78-3.85 (m, 4H), 3.07-3.12 (m, 4H); MS (ESI−) M/Z 413 (M−H)−.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)(=O)C.[OH-].[K+]>CO.O>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[CH:8][CH:7]=[C:6]2[CH2:5][OH:4])=[CH:11][CH:12]=1
Reactant: COc1ccc2cccc(COC(C)=O)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2cccc(CO)c2c1
Reaction time: 3 h

Procedure:
34.5 g (0.15 mol) of the compound obtained in Step A are dissolved in 300 ml of methanol. 35 g (4 eq) of potassium hydroxide dissolved in 35 ml of water are added with vigorous stirring. After 3 hours at room temperature, the reaction mixture is hydrolysed over a mixture of ice/concentrated hydrochloric acid. The creamy white precipitate which forms is filtered off, washed several times with ice-cold water and dried over P2O5 using a dessicator. The title alcohol is recrystallised from a mixture of CH2Cl2/cyclohexane to yield white needles.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([Mg]Br)([CH3:17])[CH3:16]>C1COCC1>[CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]([OH:14])[CH:15]([CH3:17])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccn1Cc1ccccc1
Reactant: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CC(C)C(O)c1cccn1Cc1ccccc1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To 1-benzyl-1H-pyrrole-2-carbaldehyde (0.50 g, 2.7 mmol) in THF (20 mL) at 0° C. was added a solution of i-PrMgBr (5.4 mL, 1N in THF, 5.4 mmol). The reaction mixture was warmed to room temperature and after 1.5 h it was quenched with saturated aqueous ammonium chloride, extracted with EtOAc, dried (Na2SO4) and concentrated. Column chromatography (EtOAc/hexanes, 1:4) provided 0.345 g (56%) of 1-(1-benzyl-1H-pyrrol-2-yl)-2-methylpropan-1-ol as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([B:29]([OH:34])[OH:30])=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ccc3ccccc3c2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: OB(O)c1ccc(-c2ccc3ccccc3c2)cc1
Temperature: -60 °C
Yield: 76.5 %

Procedure:
Under an argon gas atmosphere, a mixture of 50.0 g (177 mmol) of 2-(4-bromophenyl)naphthalene and 500 mL of dehydrated THF was cooled down to −60 degrees C., and added with 136 mL (212 mmol) of hexane solution of 1.56M n-butyllithium in drops while being stirred. Then, the reaction mixture was stirred for one hour at −60 degrees C. 99.6 g (529 mmol) of triisopropyl borate was dropped into the reaction solution at −60 degrees C. Subsequently, the reaction mixture was warmed up to room temperature, and stirred for 18 hours. The reaction mixture was further added with solution of hydrochloric acid to be stirred for one hour at room temperature. After the reaction, the reaction mixture was further added with toluene, so that aqueous phase thereof was eliminated. After organic phase thereof was dried with magnesium sulfate, the solvent was distilled away under reduced pressure. By crystallizing the obtained solid by toluene, 33.6 g of 4-(2-naphthyl)phenylboronic acid was obtained at an yield of 84%.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[CH2:14]([C:20](=[CH:23]OCC)C=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH3:27][O-].[Na+].CO>CCOCC>[CH2:15]([C:14]1[CH:20]=[CH:23][N:3]=[C:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][CH:6]=2)[N:4]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:27]
Reactant: CCCCCCC(C=O)=COCC
Reactant: N=C(N)c1ccc(C(N)=O)cc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1

Procedure:
0.082 mol of 4-amidino-benzoic acid amide hydrochloride, suspended in a solution of 0.082 mol of 2-n-hexyl-3-ethoxy-acrolein and 0.14 mol of sodium methylate in 150 ml. of methanol, are stirred overnight at room temperature under an atmosphere of nitrogen. The precipitate obtained by diluting the reaction mixture with 3.1 of ether is removed by filtration, washed with water until neutral and dried at 40° in a vacuum drying cabinet, whereby 17.9 g. of 4-(4-n-hexylpyrimid-2-yl)benzoic acid amide are obtained, m.p. 231.6° - 233.0°.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.Cl[C:10]1[C:11]2[S:18][CH:17]=[CH:16][C:12]=2[N:13]=[CH:14][N:15]=1>>[N:13]1[C:12]2[CH:16]=[CH:17][S:18][C:11]=2[C:10]([O:1][CH2:2][C:3]2([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]2)=[N:15][CH:14]=1
Reactant: Clc1ncnc2ccsc12
Reactant: OCC1(CO)CCC1
Product: OCC1(COc2ncnc3ccsc23)CCC1

Procedure:
The title compound was prepared using the same experimental procedure as in example 25a using [1-(hydroxymethyl)cyclobutyl]methanol and 4-chlorothieno[3,2-d]pyrimidine. 1H NMR (300 MHz, CDCl3) δ 8.70 (s, 1H), 7.87 (d, J=5 Hz, 1H), 7.49 (d, J=5 Hz, 1H), 4.69 (s, 2H), 3.61 (d, J=6 Hz, 2H), 3.36 (t, J=6 Hz, 1H), 2.01-1.82 (m, 6H). GC-MS m/z 251 (M+H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[H-].[Na+].[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.CS(C)=O>CN(C=O)C>[ClH:17].[NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]2[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1)(=[O:4])=[O:3]
Reactant: COCCOCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COCCOCCOc1cc2ncnc(C3C(=O)Nc4ccc(S(N)(=O)=O)cc43)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.2 %

Procedure:
A solution of 5-aminosulphonyloxindole (265 mg, 1.25 mmol), (prepared as described for the starting material in Example 60), in DMF (2.5 ml) was added to a suspension of sodium hydride (50 mg, 1.25 mmol, prewashed with pentane) in DMF (1.5 ml). The mixture was stirred for 30 minutes at ambient temperature and 4-chloro-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline (265 mg, 1.25 mmol), (prepared as described for the starting material in Example 74), was added followed by DMF (2 ml) and DMSO (0.5 ml). The mixture was heated at 60° C. for 45 minutes, then allowed to cool and partitioned between ether and water. The aqueous layer was separated and adjusted to pH7 with 1M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and ether, and dried under vacuum. The solid was dissolved in methylene chloride/methanol and 2.8M ethereal hydrogen chloride (1 ml) was added. The volatiles were removed by evaporation, the solid was triturated with ether, collected by filtration and dried under vacuum to give 4-(5-aminosulphonyloxindol-3-yl)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline hydrochloride (106 mg, 50%).
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C@@H:16]([O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]=2)=[CH:7][CH:6]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:18]([O:17][C@@H:16]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)=[CH:12][CH2:13][NH:14][CH2:15]1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)[C@@H](OC(=O)C(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)O[C@H]1CNCC=C1c1ccc(F)cc1

Procedure:
To a dichloromethane solution (3.0 mL) of tert-butyl (R)-4-(4-fluorophenyl)-5-(pivaloyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (1.69 g, 4.48 mmol) synthesized in Reference Synthesis Example 131, trifluoroacetic acid (1.4 mL) was added and the resultant mixture was stirred at room temperature for 2 hours. After completion of the reaction, saturated sodium bicarbonate aqueous solution was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound as a crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:27]1[N:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30]>C1COCC1>[Cl:36][C:34]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[O:9])=[CH:6][CH:7]=2)[N:35]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a suspension of (4-aminophenyl)(morpholino)methanone (9.02 g, 43.8 mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (66.7 mL, 66.7 mmol, 1M solution in THF) dropwise over 15 min. at −78° C. under nitrogen. The reaction mixture was stirred for one hour at −78° C. To the resulting brown solution was added a solution of 2,6-dichloronicotinic acid (4 g, 20.83 mmol) in THF (12 ml) dropwise at −78° C. The reaction mixture was removed from the dry ice bath and stirred overnight at rt. The resulting dark solids were washed with a small amount of THF to remove (4-aminophenyl)(morpholino)methanone on the surface, followed by the addition of water and 18 ml of 6N HCl (pH of 2). The solids were filtered and the resulting pink filter cake was washed with water (˜1 i) until the filter cake was white powder and the filtrate was colorless. The filter cake was transferred to a flask with MeOH and CH2Cl2, and dried on a rotary evaporator with MeOH to give 6.60 g of 6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinic acid as a white solid.
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:32]1(/[CH:38]=[CH:39]/[C:40](Cl)=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]([CH2:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)[C:40](=[O:41])/[CH:39]=[CH:38]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)cc2)cc1
Product: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(OCC(=O)OC)cc2)C(=O)/C=C/c2ccccc2)cc1

Procedure:
The title compound was prepared following the procedure E using methyl (4-{[(4-dec-1-ynylbenzyl)amino]methyl}phenoxy)acetate and (2E)-3-phenylacryloyl chloride (purification by flash chromatography on SiO2-c-Hex/EtOAc 9:1) as a colorless oil (64%). M+ (ESI): 552.1. HPLC, Rt: 6.1 min (purity: 99.5%). 1H NMR (CDCl3) δ: 7.85 (m, 1H), 7.47-7.12 (m, 11H), 6.90 (m, 3H), 4.65-4.52 (m, 6H), 3.82 (s, 3H), 2.41 (t, J=7.0 Hz, 2H), 1.61 (m, 2H), 1.45 (m, 2H), 1.30 (m, 8H), 0.89 (t, J=6.8 Hz, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)#[N:6]>C(OC(=O)C)(=O)C>[C:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[C:10]([N+:1]([O-:4])=[O:2])[CH:9]=1)#[N:6]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(CC#N)cc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(CC#N)cc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Concentrated nitric acid (10 mL, >69% pure) was added to acetic anhydride (100 mL) cooled to −10° C. The solution was treated portionwise with N-[4-(cyanomethyl)phenyl]acetamide (5.0 g, 28.7 mmol) at a rate which maintained an internal temperature below −5° C. The solution was stirred for 1 hour while warming to room temperature. The solution was poured into an ice/water mixture and extracted several times with ethyl acetate. The combined extracts were washed with 10% Na2CO3 and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide 4.82 g (77%) of N-[4-(cyanomethyl)-2-nitrophenyl]acetamide.